This invention relates to a novel fucosidase inhibitor. More particularly, the invention relates to the synthesis of the novel iminoheptitol, 2,6-imino-2,6,7-trideoxy-D-glycero-D-gluco heptitol.
The .alpha.-glucosidase inhibitor deoxynojirimycin (1) [Walker et al., Proc. Natl. Acad. Sci. USA 84, 8120 (1987); Tyms et al, Lancet 1987 1026; Gruters et al., Nature 330, 74 (1987)] and its alkylated derivatives [Fleet et al., FEBS Lett. 237, 128-132 (1988); Karpas et al., Proc. Natl. Acad. Sci. USA 85, 9229-9233 (1988)] inhibit human immunodeficiency virus synctium formation and virus replication and may have potential as antiretroviral agents [Sunkara et al., Biochem. Biophys. Res. Commun. 148, 206 (1987)]. See also copending application Ser. No. 07/248,461, filed Sept. 23, 1988, now U.S. Pat. No. 4,849,430, and application Ser. No. 07/249,144, filed Sept. 26, 1988.
The .beta.-D-glucopyranosyl derivative (3) of .alpha.-homonojirimycin (2) was first designed as a synthetic transition state inhibitor of .alpha.-glucosidases [Liu et al., J. Org. Chem. 52, 4717 (1987)] and is in clinical trials in relation to the treatment of diabetes mellitus [Rhinehart et al., J. Pharmacol. Expt'l. Therapeut. 241, 915 (1987)]. .alpha.-Homonojirimycin, the first example of a naturally occurring azapyranose analogue of a heptose, has recently been isolated from Omphalea diandra L. and has been demonstrated to be a potent inhibitor of digestive .alpha.-glucosidase activity [Kite et al., Tetrahedron Lett. 29, 6483 (1988)]. These azaheptoses provide the opportunity for the synthesis of a class of stable aza-disaccharides such as (3) which may confer additional potency and/or specificity in comparison with the corresponding azapyranose analogues such as deoxynojirimycin. 1,5-Dideoxy-1,5-imino-L-fucitol, also referred to as deoxyfuconojirimycin (4), first prepared by lengthy procedures from D-glucose, [Fleet et al., J. Chem. Soc. Chem. Commun. 1985, 841-842; Fleet et al., Ibid. 1988, 483-485] is a very powerful and highly specific inhibitor of a number of mammalian .alpha.-L-fucosidases. See also copending application Ser. No. 07/252,846, filed Oct. 3, 1988, now U.S. Pat. No. 4,910,310, for the synthesis of derivatives of deoxyfuconojirimycin having enzyme inhibitory activity. ##STR1## cl BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, the novel fucosidase inhibitor, 2,6-imino-2,6,7-trideoxy-D-glycero-D-gluco-heptitol (6), is synthesized in the free base form or in the acid salt form, e.g. HCl. An attempted synthesis of .alpha.-L-homofuconojirimycin (5) from diacetone mannose surprisingly resulted, instead, in the preparation of the foregoing epimeric iminoheptitol (6). In this synthesis, the catalytic hydrogenation of 6-azido-7-O-tert-butyldimethylsilyl-1,6-dideoxy-3,4-O-isopropylidene-L-gul o-heptul-2-ose followed by hydrolytic removal of the protecting groups resulted in the novel iminoheptitol (6). That is, the stereochemical result of catalytic hydrogenation of the C.dbd.N bond in a 3,4,5,6-tetrahydropyridine was determined by a bulky substituent at C-6, rather than by a 3,4-O-isopropylidene group. Thus, it has been shown that a suitable protected hydroxymethyl group can control the hydrogenation sterochemistry of the imine regardless of the other groups in the piperidine ring.